Substantial progress has been made in the prevention and treatment of breast cancer by developing new agents that target signal transduction pathways such as those stimulated by estrogen or HER2. Unfortunately, many patients' tumors become independent of these pathways indicating an urgent need to identify alternative targets. Recent clinical trials and laboratory based studies indicate that the growth hormone/insulin-like growth factor-I (GH/IGF) pathway may be important in breast cancer development. We have discovered that the Spontaneous Dwarf rat (SDR), which lacks GH due to a missense mutation in its GH gene, is nearly refractory to mammary cancer. Our hypothesis is that down regulation of the GH/IGF axis substantially retards initiation as well as promotion/progression stages of mammary carcinogenesis. Our first aim is to determine if the SDR can be made susceptible to carcinogens by treatment with GH or IGF-I administered to the SDR in vivo or to SDR mammary gland organ cultures. We also propose to compare the profile of mammotropic hormones in serum and their receptors in the mammary glands of SDRs and wild-type littermates. The second aim is to evaluate the role of the GH/IGF axis at initiation and promotion/progression stages of carcinogenesis. We will compare the SDR, the SDR treated with either GH or IGF-I, and wild-type littermates with respect to apoptosis and proliferation within the mammary gland, in response to carcinogenic insult. We will evaluate whether preneoplastic lesions develop in the mammary glands of carcinogen-exposed SDRs and examine advanced cancers for GH and IGF-I receptors. Mammary tumor transplant experiments are proposed to determine if advanced cancers are GH or IGF-I dependent. The third aim is to study the role of GH in a novel mouse model of estrogen independent mammary cancer. We will cross the C3(1)/Tag mouse, which spontaneously develops estrogen independent mammary cancers, with either the GH receptor/binding protein knockout mouse or the GH antagonist mouse. The long-term goals for this project are to determine the suitability of the GH/IGF axis as a novel target for the development of chemopreventative and/or therapeutic agents. Results from these studies could be rapidly translated to the clinic since a GH antagonist (pegvisomant) is currently in phase III trials for the treatment of acromegaly.